Paper Inggris NEW

7/28/2019 Paper Inggris NEW

1/21

The Relationship between Serum Human Immunodeficiency

Virus Type 1 (HIV-1) and Long-Term Mortality Risk in HIV-1-

Infected Children In 20 -30 old men in Jakarta 2000

By:

YOLANDA NABABAN

030.08.260

FACULTY OF MEDICINE

TRISAKTI UNIVERSITY

JAKARTA

2009

i


2/21

PREFACE

This paper titled The Relationship between Serum Human Immunodeficiency Virus

Type 1 (HIV-1) RNA Level, CD4 Lymphocyte Percent, and Long-Term Mortality Risk in

HIV-1-Infected Children in 20 -30 old men in Jakarta 2000 was created for the purpose of

completing the assignment for the Medical English II in Trisakti University, Faculty of

Medicine. In this paper is discussed all the information about the relationship between HIV-1

RNA level and CD4 lymphocyte percent, as well as their prognostic values, that may be

affected by the pathogenesis of HIV infection. By reading the content of this paper, the reader

will become more aware of the fatality of this disease and will take the steps to prevent these

disease from happening.

Many thanks and appreciation to those who have helped in the process of making thispaper. Furthermore, my apologizes if there are errors contained in this paper for it is created

during a learning process.

Jakarta, 12 04-2009

Yolanda Nababan

ii


3/21

TABLES OF CONTENTS

Preface.......................................................................................................................................ii

I. Introduction...................................................................................................................1

I.1 Background..............................................................................................................1

I.2 Methods....................................................................................................................2

I.3 Result........................................................................................................................4

I.4 Discussions.............................................................................................................13

I.5 References...............................................................................................................18

INTRODUCTION

iii


4/21

I.1 Background

Primary human immunodeficiency virus type 1 (HIV-1) infection among adults is

characterized by an initial burst of viremia, with HIV-1 RNA levels as high as 1O6-107

copies/mL, followed by a 100- to 1000-fold decline over the subsequent 2-3 months until

reaching a steady-state plateau that may persist for years [1 -3]. A number of studies among

infected adults have demonstrated that plasma RNA levels after seroconversion are

independently predictive of risk for HIV-1 disease progression; higher HIV-1 RNA levels

correlate with more rapid disease progression and elevated mortality risk, while treatment-

induced declines in RNA levels have been associated with clinical benefit [4-6]. These

studies have led to the development of treatment recommendations for infected adults based

on measurement of plasma HIV-1 RNA; RNA levels exceeding a threshold of ~ 10,000

copies/mL are viewed as indicative of the need to consider initiating therapy [7, 8].

Fewer data exist regarding HIV-1 RNA levels among infected children, particularly

regarding the relationship of RNA with long-term clinical outcome. Several studies of

perinatally infected children have shown persistent high RNA levels (s= 106 copies/mL)

throughout the first 2 years of life, with only 2- to 10-fold declines from initial peak valuesduring the first 12 months of life; these high levels may be observed despite normal CD4

lymphocyte counts and lack of symptoms [9-13]. RNA levels then appear to fall slowly until

24-36 months of age, independent of antiretroviral treatment and immunologic or clinical

status [10-12]. These findings may reflect the influence of an immature but developing

immune system that requires several years before achieving the capacity to control viral

replication to an extent similar to that observed in infected adults.

In perinatally infected children, RNA levels that are extremely elevated after 1-2

months of age (>300,000 copies/ mL) have been associated with more rapid progression to

AIDS early in life. However, because of significant overlap in RNA levels between rapid and

non-rapid progressors, no single threshold level predictive of disease progression has yet

been identified in children [11, 12].

The National Institute of Child Health and Human Development (NICHD)

Intravenous Immunoglobulin (IVIG) Clinical Trial was initiated to evaluate the effect of

IVIG versus albumin placebo for prophylaxis of bacterial infections in HIV-1-infected

iv


5/21

children. Although mortality was similar between study groups, reduction in the incidence of

infections and hospitalizations, as well as slowing of decline in CD4 lymphocytes, was

observed with IVIG treatment [14-17]. During the course of this trial, blood was collected

from patients at baseline and every 3 months during the study and sera were stored in a

central repository. Additionally, follow-up data on the vital status of enrolled children 5 years

after completion of the trial were obtained. Thus, these stored sera provide a unique oppor-

tunity to retrospectively evaluate HTV-1 KNA levels in a large HIV-1-infected pediatric

cohort with well-defined long-term clinical outcomes.

The objectives of the current analysis were to describe the distribution of baseline

HIV-1 RNA levels at study entry and changes over time in this cohort of children with mild

to moderate HIV-1 disease, to evaluate the association of long-term mortality risk with

baseline RNA level and subsequent RNA levels over time, and to evaluate the independent

contributions of HIV-1 RNA level and CD4 lymphocyte percent to long-term mortality risk.

I.2 Methods

The NICHD IVIG Clinical Trial was a randomized, double-blind placebocontrolled

phase III outpatient clinical trial of the use of IVIG for prophylaxis of bacterial infections.

The trial was conducted between March 1988 and January 1991 in 28 clinical centers in the

mainland United States and Puerto Rico. Three hundred seventy-six HIV-1 -infected,

nonhemophiliac children between the ages of 1 month and 12 years were enrolled, the

majority of whom acquired infection perinatally and had only mild to moderate symptoms of

HIV-1 disease. IVIG (Gamimune N; Miles, Berkeley, CA) was administered every 28 days to

187 patients (400 mg/kg of body weight), while 189 patients received a visually

indistinguishable placebo consisting of 0.1% albumin without preservatives in 10% maltose,

administered in an identical fashion. Children were seen monthly for examination and

infusion. During these visits, information regarding intercurrent infections and medications

was collected. Prophylaxis against Pneumocystis carinii pneumonia with a 3 consecutive day-

per-week regimen of tri-methoprim-sulfamethoxazole and use of zidovudine antiretroviral

therapy at any time after study entry were permitted, according to the prevailing medical

standard of care as determined by the patient's physician with consent of the parent or

v


6/21

guardian. Further study methods and results are given elsewhere [14-17]. Additionally, in

September 1996, each clinic site was contacted and asked to provide current vital status

information for their study patients.

Blood was collected from patients at entry to the trial and every 3 months thereafter

during the course of the trial. Serum was separated, stored at 20 to 70C, and

periodically shipped to a central repository on dry ice, where specimens were stored at

70C. All frozen specimens from children who had available baseline samples were retrieved

and tested for HIV-1 RNA, using the nucleic acid sequence-based amplification (NASBA)

assay according to manufacturer's instructions (Organon Teknika, Durham, NC). Specimens

had been stored for 4-7 years before testing. All assays were performed by a single laboratory

that was participating in the AIDS Clinical Trials Group HIV-1 Virology Quality Assurance

program [18]. Testing was done over a 6-month period in late 1995 and early 1996.

The NASBA assay involves extraction of nucleic acid by binding to silicon dioxide

particles. The process can be used for testing many body fluids, including serum and plasma.

HIV-1 RNA is amplified by an isothermal amplification procedure and quantified by

coamplification with internal kit RNA calibrator standards of 10,000, 100,000, and 1,000,000

copies/mL. The quantity of amplified RNA was measured by means of an

electrochemiluminescence technique, and results were expressed as copies of HIV-1 RNA

per milliliter. The assay can detect up to a 4 log,0 variation in copy number; for the input

volume of 100 yuL of serum used in this study, the lower limit of detection was 4000

copies/mL. Evaluation of interassay precision at the central laboratory indicated an interassay

SD of 0.18 Iog10.

CD4 lymphocyte percent and absolute count were measured at study entry and every

3 months during the trial. Flow cytometry was performed locally at laboratories participating

in one of several national quality assurance programs. Procedures for performance of flow

cytometric evaluations during the study have been described [16]. Because CD4 lymphocyte

percent exhibits less measurement variability than the absolute count and varies less by age

[19], CD4 cell percent rather than absolute count was used in the analyses.

The evaluation included baseline HIV-1 RNA copy number, baseline CD4

lymphocyte percent, and two measures of change in HIV-1 RNA copy number: absolute

vi


7/21

change (final value - baseline value) and yearly rate of change (slope of least squares

regression line). The relationship between HIV-1 RNA level and age was assessed with a

mixed-effects repeated-measures model. Intrapatient changes from baseline were assessed

with the t test. The relationship of baseline HIV-1 RNA level and changes in RNA levels

with mortality was evaluated with the %2 test for linear trend and Kaplan-Meier analyses.

Proportional hazard analyses using time-fixed (baseline values) and time-dependent (all

available measurements) methods were used to evaluate the independent relationship of RNA

level and CD4 lymphocyte percent with mortality. Time-fixed models were adjusted for

baseline value of the primary independent variable, age at baseline, and IVIG or placebo

treatment group; time-dependent models were adjusted for all available measurements of the

primary independent variable, age at time of measurement, zidovudine use at time of

measurement, and IVIG or placebo treatment group.

I.3 Results

Study population. Of the 376 children in the trial, 254 (68%) had 1 sample available

for testing. Characteristics of the analysis cohort are shown in table 1.

Children in the analysis cohort were similar to the overall study cohort in terms of

sex, race or ethnicity, age at entry, entry CD4 lymphocyte count and percent, prior history of

AIDS-defining infections, use of zidovudine therapy and tri-methoprim-sulfamethoxazole P.

carinii pneumonia prophylaxis during the study, duration of follow-up, and percentage of

mortality. Forty-one children (16%) died during the course of the trial, and an additional 51

children (20%) died during the extended follow-up period.

Table 1. Characteristics of children included in the HIV-1 RNA analysis cohort

(children with available baseline serum specimens) compared with characteristics of the

overall National Institute of Child Health and Human Development Intravenous

Immunoglobulin Clinical Trial study population.

Characteristic Analy

sis cohort

Overall

study cohort

vii


8/21

No. of patients

% male

% minority race or ethnicity

% with perinatal infection

Age at entry (%)

1 year

1-2 years

2-6 years

>6 years

Mean years (SD)

Mean CD4 lymphocyte values at

entry

Absolute count (/mm3) %

History of AIDS-defining infection at

entry (%)

Opportunistic infection

Recurrent serious bacterial infection

Opportunistic or recurrent serious

bacterial infection % who used zidovudine

during study % who used trimethoprim-

sulfamethoxazole for PCP

prophylaxis (cumulative)

Mean years of vital status follow-up

(SD)

No. of deaths (%)

Total no. of serum samples

Mean no. of serum samples of

patients

254

55.5

92.1

90.2

12.2

20.1

53.1

14.6

3.41

(2.32)

1105

25.1

3.9

15.7

18.1

44.1

51.2

5.1

(2.8)

92

(36.2)

1124

4.4

376

54.8

91.8

91.5

13.6

19.7

52.9

13.8

3.36

(2.33)

1127

25.3

6.4

19.1

22.3

43.6

46.5

5.0 (2.9)

149 (39.6)

NOTE. PCP = Pneumocystis carinii pneumonia.

viii


9/21

Response to the vital status survey was received from 100% of trial sites. Of the 213

children in the HIV-1 RNA analysis cohort who were alive at the end of the clinical trial, 199

(93.4%) had updated vital status information available.

HIV-1 RNA. A wide range of HIV-1 RNA levels were observed at baseline, from

undetectable ( 500,000 copies/mL.

Despite prolonged serum storage, the NASBA assay demon-stated a >4-fold

difference in logio baseline HIV-1 RNA levels in this population. In addition, the

distributions of mean and median RNA levels were similar, regardless of year of study entry,

further suggesting that length of storage did not greatly affect serum HIV-1 RNA levels when

measured by the NASBA assay. Most of the children entered in 1988 and 1989 (136 and 87,

respectively); entry characteristics (mean age, CD4 cell percent, and history of AIDS-

defining infections) were similar for children entering in each year. The 31 children who

entered in 1990 had ages and CD4 cell percents similar to those of the children who entered

in the previous years but were somewhat less likely to have a history of AIDS-defining

infections at entry. Geometric mean baseline RNA levels were 117,175 copies/mL (logio

value, 105'07) for children who entered in 1988, 88,281 (10495) for those who entered in

1989, and 102,527 (105 01) for those who entered in 1990.

In a longitudinal evaluation of geometric mean HIV-1 RNA levels by age at time of

measurement, RNA levels were highest among infants 400,000 copies/mL for infants < 12 months of age (figure 2). Although there was a

slow decrease in HIV-1 RNA levels with increasing age, mean levels did not decline to

1,000,000 HTV-1 RNA copies/mL, respectively). In contrast, for children >2 years old,

mortality risk increased when HTV-1 RNA exceeded 100,000 copies/mL (24%, 25%, 56%,

and 67% for =slO,000, 10,001-100,000, 100,001-1,000,000^ and > 1,000,000 HIV-1 RNA

copies/mL, respectively).

In addition to the percentage of subjects who died during the study, the mortality rate

was also examined. Table 2 provides the mortality rate (per 100 person-years) for subjects

with different baseline HIV-1 RNA levels. The same gradient observed for mortality

xi


12/21

percentages was seen for mortality rates; mortality risk increased with increasing baseline

HIV-1 RNA levels. The mortality rate for subjects with baseline HIV-1 RNA > 100,000

copies/mL was 2.8 times greater than the rate for subjects with HIV-1 RNA levels below this

value (95% CI, 1.8-4.4; P < .001).

Figure 3 A depicts a Kaplan-Meier analysis of the probability of survival by baseline

HIV-1 RNA categories of^l 0,000, 10,001-100,000, 100,001-1,000,000, and > 1,000,000 cop-

ies/mL. The probability of survival during the study for children with baseline HIV-1 RNA

levels < 10,000 copies/mL was similar to that observed for children with baseline levels of

10,001-100,000 copies/mL (P = .82). However, there was a significant decrease in probability

of survival for those with baseline levels of 100,001-1,000,000 copies/mL compared with

those with baseline levels =s 100,000 copies/mL (P = .003) and for those with baseline levels

> 1,000,000 copies/ mL compared with those with baseline values =S 1,000,000 copies/mL

(P < .001).

The positive predictive value of different baseline HIV-1 RNA thresholds for

mortality risk was evaluated (table 3). This measure reflects the percentage of patients with

baseline HIV-1 RNA levels above a chosen cutpoint who subsequently died during the study

or extended follow-up period. As expected, the positive predictive value increased as the

HIV-1 RNA cutpoint increased. However, the positive predictive value, which is determined

by the prevalence of the outcome of interest and the sensitivity and specificity of the

screening test, was relatively low for the various cutpoints. Use of a baseline HIV-1 RNA

level > 100,000 copies/mL as the threshold for assessing mortality risk produced a test

sensitivity of 67.4% and a specificity of 59.9%. These values, combined with the overall

mortality percentage of 36.2%, yielded a positive predictive value of 48.8%.

The relative risk of death (RR) associated with having baseline HTV-1 RNA values

above versus below selected thresholds also is shown in table 3. At 10,000 copies/mL, the RR

was elevated but not statistically significant. Changing the threshold value-from 10,000 to

100,000 copies/mL increased the RR to 2.1 (95% CI, 1.4-3.0). There was only a slight

increase in the RR as the baseline HIV-1 RNA threshold was raised to 1,000,000 copies/mL.

HTV-1 RNA in HIV-1-Infected Children

Table 2. Association of baseline HIV-1 RNA and CD4 cell percent with mortality

during study and follow-up.

xii


13/21

Baselin

e

N

o. ofdeaths

N

o. ofpatients

Mortalit

y percent*

Person

-time

Mortalit

y rate

HIV-1

RNA level

(copies/mL)

10.00

0

10.000

1-100.000

100.00

1-1.000.000

>

1.000.000

Total

CD4cell percent

25%

15%-

24.9%

< 15%

Total

9

21

37

25

92

31

16

44

91

40

87

92

35

25

4

13

0

62

60

252

22.5

24.1

40.2

71.4

36.2

23.8

25.8

73.3

36.1

243.30

506.87

453.13

96.90

1300.2

1

761.10

341.12

192.18

1294.4

0

3.70

4.14

8.17

25.80

7.08

4.07

4.69

22.90

7.03

* P < .001, x2 test for trend, for both HIV-1 RNA level and CD4 cell percent.

f Person-years of follow-up.

J Per 100 person-years of follow-up.

Excludes 2 subjects who did not have an available baseline CD4 cell

measurement.

Subjects were grouped into quartiles on the basis of the value of their average rate of

change (i.e., the slope). The mortality percentage among subjects in the fourth quartile

(largest HTV-1 RNA increase) was greater than the mortality percentage in the first three

xiii


14/21

quartiles (59.6% vs. 26.9%, P < .001). Subjects also were grouped on the basis of whether

their average rate of change in HIV-1 RNA level increased over the study (i.e., slope >0.0) or

decreased or remained constant (i.e., slope =sO.O). The mortality percentage among those

who had increasing HIV-1 RNA levels was 1.8 times greater than that among the group with

decreasing or constant HIV-1 RNA levels (95% CI, 1.3-2.6; P = .001). Similar results were

seen when the difference (i.e., final value baseline value) was used as a measure of intra-

individual change.

To further examine the relationship between HIV-1 RNA values and mortality, while

controlling for potential confounding covariates, proportional hazards models were

constructed. Table 4 presents the mortality risk ratios per Iog10 difference in HIV-1 RNA

values. Time-fixed and time-dependent models were used that included only HIV-1 RNA

(unadjusted) as well as models that controlled for study treatment group, age, and zidovudine

use. The risk ratios per 1 Iog10 difference in HIV-1 RNA from these models varied from 2.2

to 3.3 and were statistically significant in each model.

CD4 lymphocyte percent. - The mean baseline CD4 cell count among the analysis

cohort was 1105/mm3 (SD, 892/ mm3). The mean and median baseline CD4 lymphocyte per-

cents were 25.1% and 25.0%, respectively.

The percentages of deaths and the mortality rate during the study according to the

baseline CD4 lymphocyte percent is shown in table 2. Both measures indicate a strong

relationship between decreasing CD4 cell percent and increasing mortality risk.

Survival curves for subjects with baseline CD4 lymphocyte percents of


15/21

shown in figure 4 (Pearson correlation coefficient, -0.12; P = .061). Thus, baseline CD4

lymphocyte percent does not provide an accurate indication of the specific baseline HIV-1

RNA level and vice versa.

The joint relationship of HTV-1 RNA and CD4 lymphocyte percent with mortality is

given in table 5. Subjects were divided into groups on the basis of the combination of their

baseline HTV-1 RNA results (> 100,000 or ss 100,000 copies/mL) and CD4 lymphocyte

percents (5=15% or


16/21

I.4 Discussion

A wide range of HIV-1 RNA levels were observed for children in this study, from


17/21

Although there was an inverse relationship between HIV-1 RNA level arid CD4

lymphocyte percent, the correlation was only modest, 'and a 3-4 Iog10 range in number of

HIV-1 RNA copies was observed for any selected CD4 lymphocyte percent.

Table 4. Time-fixed and time-dependent proportional hazards models: relationship of

HIV-1 RNA level, CD4 cell percent, and combined effect of HIV-1 RNA level and CD4

lymphocyte percent with mortality.

Primary

independent

variable s

Time-fixed Time-dependent

Unadjuste Adjust Unadj Adjusted

HlV-l

RNA level

2.16

(1.67-2.81)

2.74

(2.06-3.65)

1.42 1.29-

2.74

(2.16-3.47)

1.54 1.39-

3.32

(2.54-4.33)

NOTE. Data are mortality risk ratio per 1 logic increase in HIV-1 RNA level and per

5 percentage point decrease in CD4 lymphocyte percent (95% confidence interval). Time-

fixed, unadjusted model includes only baseline value of primary independent variable(s);time-fixed, adjusted model includes baseline value of primary independent variable), plus

treatment group (intravenous immunoglobulin or placebo) and age at baseline; time-

dependent, unadjusted model includes all available measurements of primary independent

variable(s); time-dependent, adjusted model includes all available measurements of primary

independent variable(s), plus treatment group, age at time of measurement, and zidovudine

use at time of measurement. P < .001 for all comparisons.

This poor correlation of CD4 lymphocyte count with viral RNA load has also been

observed in cohorts of infected adults [5, 21].

The prolonged follow-up (3=5 years) available in this study enables evaluation of the

association of HIV RNA levels and CD4 cell percents with long-term clinical outcome that is

unavailable in any published pediatric cohort data. Higher baseline HIV-1 RNA levels were

associated with increased long-term mortality risk. This is similar to what has been observed

among infected adults [1, 3, 5]. However, defining a discrete HIV-1 RNA cutpoint for

potential clinical decision-making is difficult, as evidenced by the poor predictive value of

xvii


18/21

HIV-1 RNA levels < 1,000,000 copies/mL for mortality risk. The HIV-1 RNA threshold of

10,000 copies/mL suggested as a cutoff for considering initiation of therapy for infected

adults [7] had a very poor predictive value for mortality among this cohort of infected

children, with a positive predictive value of only 39%. When a threshold of 100,000

copies/mL was used, a 2-fold RR was seen between subjects above this cutpoint compared

with that for subjects below this cutpoint. The positive predictive value, however, was still

only 49%. Additionally, because of age-related changes in HIV-1 RNA early hi life, the

prognostic value of specific RNA levels may differ by age.

In studies of infected adults, an increase in HIV-1 RNA levels over time has been

associated with elevated mortality risk, and therapy-related declines in RNA levels have been

associated with improved prognosis [5, 6, 22, 23]. In this pediatric cohort, there also was an

association between increases in HIV-1 RNA levels observed during the clinical trial and

elevated long-term mortality risk. It is important to note that this pediatric clinical trial was

conducted during a time when few antiretroviral therapies were available for children.

Table 5.

xviii


19/21

Association of baseline HIV-1 RNA level and CD4 lymphocyte percent with

mortality during study.

HIV-1 RNA

level(copies/mL)

CD4

cell percent

No.

of deaths

No. of

patients

Morta

lity (%)

100,000

> 100,000

100,000

> 100,000

15

15


20/21

lymphocyte measurement obtained at the same time. After a subject's immune system has had

time to be affected by the infection, however, immunologic measures are likely to become

more relevant. This study group was first examined an average of almost 3.5 years after

infection, and both HIV-1 RNA and CD4 lymphocyte levels were independent and

complementary markers of disease stage. In many instances, a clinician may not examine a

patient until several years after the initial infection. Therefore, both markers should be

considered together for decision-making regarding therapy and evaluation of response to

antiretroviral agents.

xx


21/21

References1. Katzenstein TL, Pedersen C, Nielsen C, Lundregren JD, Jakobsen PH,

Gersetof J. Longitudinal serum HIV RNA quantification : correlation to viral

phenotype at seroconversion and clinical outcome. AIDS 1996; 10 :167-73

2. Henrard DR, Philips JF, Muenz LR, et al. Natural history of HIV-1 cell-free

viremia JAMA 1995;274:554-8

3. Havlir DV, Rihman FF. Viral dynamics of HIV : implications for drug

developmeny and therapeutic strategies. Ann Intern Med 1996;124:984-94

xxi

Documents

Paper Inggris NEW